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Abstract Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as − 10 kcal/mol while the docking score of Oxymorphone was predicted as − 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (− 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (− 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as − 36.8323 ± 3.4565, and − 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.

Antimicrobial resistance could threaten millions of lives in the immediate future. Antimicrobial peptides (AMPs) are an alternative to conventional antibiotics practice against infectious diseases. Despite the potential contribution of AMPs to the antibiotic’s world, their development and optimization have encountered serious challenges. Cutting-edge methods with novel and improved selectivity toward resistant targets must be established to create AMPs-driven treatments. Here, we present AMPTrans-lstm, a deep generative network-based approach for the rational design of AMPs. The AMPTrans-lstm pipeline involves pre-training, transfer learning, and module identification. The AMPTrans-lstm model has two sub-models, namely, (long short-term memory) LSTM sampler and Transformer converter, which can be connected in series to make full use of the stability of LSTM and the novelty of Transformer model. These elements could generate AMPs candidates, which can then be tailored for specific applications. By analyzing the generated sequence and trained AMPs, we prove that AMPTrans-lstm can expand the design space of the trained AMPs and produce reasonable and brand-new AMPs sequences. AMPTrans-lstm can generate functional peptides for antimicrobial resistance with good novelty and diversity, so it is an efficient AMPs design tool.

The number of new cases of hepatocellular carcinoma (HCC) worldwide reached 910,000, ranking the sixth, 80% HCC is associated with viruses, so exploring the molecular mechanism of viral carcinogenicity is imperative. The study showed that both HBV and HCV associated HCC and non-viral HCC have the same molecular phenotype (low gene expression and inhibition of immune pathways), but in the tumor immune micro-environment, there is excessive M2-type macrophage polarization in virus-associated hepatocellular carcinoma. To address this phenomenon, the data sets were analyzed and identified five hub genes (POLR2A, POLR2B, RPL5, RPS6, RPL23A) involved in viral gene expression and associated with PI3K-Akt-mTOR pathway activation by six algorithms. In addition, numerous studies have reported that M2-type macrophages participate in the hepatic fibro-pathological process of the development of HCC and are regulated by the PI3K-Akt-mTOR pathway. On this basis, the study showed that hepatitis virus causes abnormal expression of hub genes, leading to the activation of the pathway, which in turn promote the differentiation of M2-type macrophages and eventually promote the formation of liver fibrosis, leading to the occurrence of HCC. In addition, these hub genes are regulated by transcription factors and m6A enzyme, and have good prognosis and diagnostic value. With regard to drug reuse, the results suggest that patients with virus-related HCC for whom Cytidine triphosphate disodium salt and Guanosine-5’-Triphosphate are used as supplementary therapy, and may have a better prognosis. In conclusion, the study has identified novel molecules that are carcinogenic to hepatitis viruses and are expected to serve as molecular markers and targets for diagnosis and treatment.

Dielectric constant (DC, ε) is a fundamental parameter in material sciences to measure polarizability of the system. In industrial processes, its value is an imperative indicator, which demonstrates the dielectric property of material and compiles information including separation information, chemical equilibrium, chemical reactivity analysis, and solubility modeling. Since, the available ε-prediction models are fairly primitive and frequently suffer from serious failures especially when deals with strong polar compounds. Therefore, we have developed a novel data-driven system to improve the efficiency and wide-range applicability of ε using in material sciences. This innovative scheme adopts the correlation distance and genetic algorithm to discriminate features’ combination and avoid overfitting. Herein, the prediction output of the single ML model as a coding to estimate the target value by simulating the layer-by-layer extraction in deep learning, and enabling instant search for the optimal combination of features is recruited. Our model established an improved correlation value of 0.956 with target as compared to the previously available best traditional ML result of 0.877. Our framework established a profound improvement, especially for material systems possessing ε value >50. In terms of interpretability, we have derived a conceptual computational equation from a minimum generating tree. Our innovative data-driven system is preferentially superior over other methods due to its application for the prediction of dielectric constants as well as for the prediction of overall micro and macro-properties of any multi-components complex.

Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (ΔG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK.

Photodynamic therapy (PDT) is a rapidly evolving area of cancer management against solid tumors. PDT is either administrated by injecting photosensitizer (porphyrins) or by accumulation of intracellular protoporphyrin IX via the inhibition of human Protoporphyrinogen Oxidase IX (hPPO). In this study, novel inhibitors of hPPO have been investigated by integrating virtual screening, molecular docking, and molecular dynamics (MD) simulation. A ligand-based pharmacophore was generated from a training set of 22 inhibitors of hPPO. The selected pharmacophore had four chemical features including three hydrogen bond acceptors and one hydrophobic. The pharmacophore was characterized by highest correlation coefficient of 0.96, cost difference of 53.20, and lowest root mean square deviation of 0.73. The resultant pharmacophore was validated by Fischer’s Randomization and Test Set Validation methods. The validated pharmacophore was used as a 3D query to screen chemical databases including NCI, Asinex, Chembridge, and Maybridge. The screening of chemical databases and the subsequent application of Lipinski’s Rule of Five, and ADMET Assessment Test, retrieved 1176 drug-like compounds. The drug-like compounds were subjected to molecular docking studies in the active site of hPPO to eliminate false positive hits and to elucidate their true binding orientation. Top three candidate molecules with high docking scores and hydrogen bond interactions with catalytic active residues were selected as best candidate inhibitors against hPPO. The binding stability of selected candidate inhibitors was evaluated by MD simulation. The MD simulation of hits portrayed strong hydrogen bonds and key hydrophobic interactions with catalytic active residues of hPPO including R59, R97, G159, G332 and flavin moiety of FAD (coenzyme of hPPO). Our study predicts three hit compounds against hPPO, which could possibly accumulate high concentration of protoporphyrinogen-IX, and thereby acting as an intracellular photosensitizer against tumor cells through photodynamic therapy. Keywords: Photodynamic therapy (PDT), hPPO Inhibition, Virtual screening, Pharmacophore modeling, Molecular docking simulation, Molecular dynamics (MD) simulation

Following publication of the original article [1], the authors reported errors in Figure 3, Figure 14a, Figure 18, Figure 19b, Additional file 3 and Additional file 7.

OBJECTIVE: To determine the outcomes of gross mobility after physical therapy interventions undertaken at the Paraplegic Center Peshawar, Khyber Pakhtunkhwa, Pakistan for functional recovery of patients with spinal cord injuries (SCI). METHODS: This sequential intervention trial was conducted from June 2016 to July 2017, at Paraplegic Center Peshawar, Khyber Pakhtunkhwa, Pakistan. Using consecutive sampling technique, a total of 76 persons with paraplegia were included. Persons with tetraplegia were excluded. Motor relearning program (MRP) was applied three hours per day in a standardized intervention, 3 days per week. The post intervention evaluation was done by using spinal cord independence measure (SCIM) scale. Data was analyzed in SPSS version 20.0, where the mean score of post intervention (for each six visits) was compared to see the improvement. ANOVA was used and a p value of 100meters), wheelchair-car transfer & ground-wheelchair transfers showed significant improvement (p

Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults. Cdk5/p25 abnormally phosphorylates tau protein, and induces tau-associated neurofibrillary tangles in neurological disorders. Therefore, the pharmacological inhibition of Cdk5/p25 alleviates tau-associated neurological disorders. Herein, computational simulations probed two candidate inhibitors of Cdk5/p25. Structure-based pharmacophore investigated the essential complementary chemical features of ATP-binding site of Cdk5 in complex with roscovitine. Resultant pharmacophore harbored polar interactions with Cys83 and Asp86 residues and non-polar interactions with Ile10, Phe80, and Lys133 residues of Cdk5. The chemical space of selected pharmacophore was comprised of two hydrogen bond donors, one hydrogen bond acceptor, and three hydrophobic features. Decoy test validation of pharmacophore obtained highest Guner-Henry score (0.88) and enrichment factor score (7.23). The screening of natural product drug-like databases by validated pharmacophore retrieved 1126 compounds as candidate inhibitors of Cdk5/p25. The docking of candidate inhibitors filtered 10 molecules with docking score >80.00 and established polar and non-polar interactions with the ATP-binding site residues of Cdk5/p25. Finally, molecular dynamics simulation and binding free energy analyses identified two candidate inhibitors of Cdk5/p25. During 30 ns simulation, the candidate inhibitors established

Abstract Background Antibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported. Methods Computational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis. Results Based on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100 ns employing GROMACS package. Conclusions Finally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used as fundamental platforms for novel SaHPPK inhibitor development.

Abstract Background Angiogenesis is a process of formation of new blood vessels and is an important criteria demonstrated by cancer cells. Over a period of time, these cancer cells infect the other parts of the healthy body by a process called progression. The objective of the present article is to identify a drug molecule that inhibits angiogenesis and progression. Methods In this pursuit, ligand based pharmacophore virtual screening was employed, generating a pharmacophore model, Hypo1 consisting of four features. Furthermore, this Hypo1 was validated recruiting, Fischer’s randomization, test set method and decoy set method. Later, Hypo1 was allowed to screen databases such as Maybridge, Chembridge, Asinex and NCI and were further filtered by ADMET filters and Lipinski’s Rule of Five. A total of 699 molecules that passed the above criteria, were challenged against 4AG8, an angiogenic drug target employing GOLD v5.2.2. Results The results rendered by molecular docking, DFT and the MD simulations showed only one molecule (Hit) obeyed the back-to-front approach. This molecule displayed a dock score of 89.77, involving the amino acids, Glu885 and Cys919, Asp1046, respectively and additionally formed several important hydrophobic interactions. Furthermore, the identified lead molecule showed interactions with key residues when challenged with CDK2 protein, 1URW. Conclusion The lead candidate showed several interactions with the crucial residues of both the targets. Furthermore, we speculate that the residues Cys919 and Leu83 are important in the development of dual inhibitor. Therefore, the identified lead molecule can act as a potential inhibitor for angiogenesis and progression.

OBJECTIVE: to determine mortality and its associated factors in patients with spinal cord injuries (SCI), presenting to Paraplegic Center Peshawar, Pakistan. METHODS: In this retrospective study, clinical records of SCI patients, admitted to Paraplegic Center from January 2011 to March 2017 were evaluated. SCI patients who died during this period, irrespective of their age, gender, duration of SCI and number of readmissions were included in study. Demographic information, clinical characteristic and complications in eligible patients were recorded and analyzed. RESULTS: Out of 62 patients, 46 (74.2%) were males. Mean age of patients was 41.7±17.3 years. Twenty-two (35.5%) patients aged ≤30 years & 20 (32%) patients aged >50 years. The most common cause of SCIs was fall from height (n=23, 37.1%), followed by road traffic accident (n=17, 27.4%) and firearm injury (n=11, 17.7%). About 51.6% of patients (n=32) had complete thoracic paraplegia, 30.6% (n=19) had complete cervical tetraplegia and 8.1% (n=5) had incomplete cervical tetraplegia. Complications and co-morbid conditions included pressure ulcers (n=53; 85.5%), limb fractures (n=7 11.3%), deep venous thrombosis (n=3; 4.8%), hepatitis (n=2; 3.2%) and injury to brachial plexus (n=1; 1.6%). Twenty-two (35.5%) patients underwent spine fixation surgery while forty (64.5%) patients were managed conservatively. Majority of the patients (n=51, 82.3%) died within the first year of SCI. CONCLUSION: Relatively younger patients were predominant and complete thoracic paraplegia was the commonest SCI level. Presence of pressure ulcers, limb fractures and deep venous thrombosis in patients with SCI were major contributing factors to morbidity leading to mortality in our patients.

Drug resistance is a core issue in cancer chemotherapy. A known folate antagonist, methotrexate (MTX) inhibits human dihydrofolate reductase (hDHFR), the enzyme responsible for the catalysis of 7,8-dihydrofolate reduction to 5,6,7,8-tetrahydrofolate, in biosynthesis and cell proliferation. Structural change in the DHFR enzyme is a significant cause of resistance and the subsequent loss of MTX. In the current study, wild type hDHFR and double mutant (engineered variant) F31R/Q35E (PDB ID: 3EIG) were subject to computational study. Structure-based pharmacophore modeling was carried out for wild type (WT) and mutant (MT) (variant F31R/Q35E) hDHFR structures by generating ten models for each. Two pharmacophore models, WT-pharma and MT-pharma, were selected for further computations, and showed excellent ROC curve quality. Additionally, the selected pharmacophore models were validated by the Guner-Henry decoy test method, which yielded high goodness of fit for WT-hDHFR and MT-hDHFR. Using a SMILES string of MTX in ZINC15 with the selections of ‘clean’, in vitro and in vivo options, 32 MTX-analogs were obtained. Eight analogs were filtered out due to their drug-like properties by applying absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment tests and Lipinski’s Rule of five. WT-pharma and MT-pharma were further employed as a 3D query in virtual screening with drug-like MTX analogs. Subsequently, seven screening hits along with a reference compound (MTX) were subjected to molecular docking in the active site of WT- and MT-hDHFR. Through a clustering analysis and examination of protein-ligand interactions, one compound was found with a ChemPLP fitness score greater than that of MTX (reference compound). Finally, a simulation of molecular dynamics (MD) identified an MTX analog which exhibited strong affinity for WT- and MT-hDHFR, with stable RMSD, hydrogen bonds (H-bonds) in the binding site and the lowest MM/PBSA binding free energy. In conclusion, we report on an MTX analog which is capable of inhibiting hDHFR in wild type form, as well as in cases where the enzyme acquires resistance to drugs during chemotherapy treatment.

Ischemic stroke is characterized by permanent or transient obstruction of blood flow, which initiates a cascading pathological process, starting from acute ATP loss to subsequent membrane depolarization, glutamate excitotoxicity, and calcium overload. Melatonin is a potent antioxidant that exerts protective effects in different experimental stroke models. In this study, melatonin effects were demonstrated by a proteomic and in silico approach. The proteomic study identified differentially expressed proteins by 2D gel electrophoresis in the striatum 24 h after middle cerebral artery occlusion. Proteomic analysis revealed several proteins with aberrant expression and was validated by western blot and immunofluorescence analysis. Homology modeling was performed to build 3D structures for γ-enolase, thioredoxin (TRX), and heat shock 60 (HSP60) by the template crystal structures using a protein data bank as a sequence database. The structure refinement of each model was achieved by energy minimization via molecular dynamic simulation, and the generated models were further assessed for stability by Procheck and ProSA. The models were processed for docking analysis using AutoDock Vina, and post-docking analysis was determined by discovery studio. The proteomic study showed decreased expression of γ-enolase, TRX, and protein phosphatase 2A subunit B and increased expression of collapsin response mediator protein 2 and HSP60 in the striatum after ischemic injury. Treatment with melatonin modulated the expression profiles of these proteins. This study demonstrated the neuroprotective role of melatonin in the ischemic striatum using a proteomic and in silico approach. Collectively, melatonin may act in a multimechanistic way by modulating the expression of several proteins in the ischemic striatum.

ABSTRACT OBJECTIVES: to present demographic details, nature of injury, clinical characteristics of patients admitted to Paraplegic Centre, Peshawar, Pakistan who sustained spinal cord injury (SCI) due to bomb blasts attacks (BBA). METHODS: This retrospective quantitative study was conducted on 91 patients who sustained SCI due to BBA. These patients were admitted to Paraplegic Centre, Peshawar from 2007 to September 2016. Data about demographic information, neurological level, ASIA impairment scale, clinical characteristics, complications and other associated problems of patients were retrieved. RESULTS: Out of 91 patients, 75 (82.4%) were males and 16 (17.6%) were females with mean age of 28.3±11.0 years. Majority of the patients were from district Swat (14.3%) followed by Peshawar (12.1%). In 72 (79.1%) cases, SCI was caused by penetrating fragments (splinters/shrapnel). Forty one (45.1%) patients had complete transaction at thoracic level. Fifty nine (64.8%) patients had wounds at multiple sites of body. Seventy seven (84.6%) patients had ASIA impairment scale ‘A’. Common associated injuries included fractures in upper limbs (9.9%) and lower limbs (6.6%). Twenty three (25.3%) patients had laparotomy for visceral injuries. Sixty seven (73.7%) patients had pressure sores. Eighty eight (96.7%) patients completed rehabilitation program, 2 (2.2%) patients left hospital without completing rehabilitation program and one (1.1%) patient died during hospitalization. CONCLUSION: The main cause of SCI due to BBA was penetration fragments. Male population is more exposed to these injuries compared to female. Moreover, SCI due to BBA was associated with injuries to other parts of body. Pressure sores were the most frequent secondary complication. Key words: Spinal Cord Injury (MeSH), Spinal Injury (MeSH), Bomb Blast Attacks (Non-MeSH), Terrorism (MeSH), Suicide bombing (Non-MeSH), Mass Casualty Incidents (MeSH)

Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop new drugs to combat the disease. In this pursuit, the 3D QSAR ligand-pharmacophore (pharm 1) and receptor-based pharmacophore (pharm 2) search was initiated to retrieve the candidate compounds from universal natural compounds database. The validated models were allowed to map the universal natural compounds database. The obtained lead candidates were subjected to molecular docking against cysteine protease (PDB code: 1ME3) employing -Cdocker available on the discovery studio. Subsequently, two Hits have satisfied the selection criteria and were escalated to molecular dynamics simulation and binding free energy calculations. These Hits have demonstrated higher dock scores, displayed interactions with the key residues portraying an ideal binding mode complemented by mapping to all the features of pharm 1 and pharm 2. Additionally, they have rendered stable root mean square deviation (RMSD) and potential energy profiles illuminating their potentiality as the prospective antichagastic agents. The study further demonstrates the mechanism of inhibition by tetrad residues compromising of Gly23 and Asn70 holding the ligand at each ends and the residues Gly65 and Gly160 clamping the Hits at the center. The notable feature is that the Hits lie in close proximity with the residues Glu66 and Leu67, accommodating within the S1, S2 and S3 subsites. Considering these findings, the study suggests that the Hits may be regarded as effective therapeutics against Chagas disease.

Aquatic bodies contaminated by heavy metals (HMs) are one of the leading issues due to rapidly growing industries. The remediation of using algae and hydrophytes acts as an environmentally friendly and cost effective. This study was performed to investigate the pollution load, especially HMs, in the wastewater of the Gadoon Industrial Estate and to utilize the hydrophytes (Typha latifolia (TL) and Eicchornia crassipes (EI)) and algae (Zygnema pectiantum (ZP) and Spyrogyra species (SS)) as bioremediators. The wastewater was obtained and assessed for physiochemical parameters before treating with the selected species. The pot experiment was performed for 40 days. Then the wastewater samples and selected species were obtained from each pot to analyze the metal removal efficiency and assess for metal concentrations using atomic absorption spectrophotometry. The dissolved oxygen (DO; 114 mg/L), total suspended solids (TSS; 89.30 mg/L), electrical conductivity (EC; 6.35 mS/cm), chemical oxygen demand (COD) (236 mg/L), biological oxygen demand (BOD; 143 mg/L), and total dissolved solids (TDS; 559.67 mg/L), pH (6.85) were analyzed. The HMs were noted as Zn (5.73 mg/L) and Cu (7.13 mg/L). The wastewater was then treated with the species, and significant reductions were detected in physicochemical characteristics of the wastewater such as DO (13.15–62.20%), TSS (9.18–67.99%), EC (74.01–91.18%), COD (25.84–73.30%), BOD (21.67–73.42%), and TDS (14.02–95.93%). The hydrophytes and algae removed up to 82.19% of the Zn and 85.13% of the Cu from the wastewater. The study revealed that the hydrophytes and algae significantly decreased the HM levels in the wastewater (p ≤ 0.05). The study found TL, EI, ZP, and SS as the best hyper accumulative species for Zn and Cu removal from wastewater. The HMs were removed in the order of Cu > Zn. The most efficient removal for Cu was found by Typha latifolia and Zn by Zygnema pectiantum. It was concluded that bioremediation is an environmentally friendly and cost-effective technique that can be used for the treatment of wastewater due to the efficiency of algae and hydrophytes species in terms of HM removal. [ABSTRACT FROM AUTHOR]